Hand, foot, and mouth disease (HFMD) is caused by several members of the human enterovirus A (HEV-A) group. It is generally a self-limiting infection affecting mostly children and is characterized by ulcers and vesicles on the hands, feet and oral cavity. However, a more severe form of disease may occur with neurological symptoms such as meningitis, encephalitis, polio-like paralysis, and brain stem encephalitis leading to pulmonary edema and death (Huang, C C et al., (1999) N Engl J Med 341: 936-942; Chang, L Y et al., (1998) Lancet 352: 367-368; and Ooi, M H et al., (2009) BMC Infect Dis 9: 3). Since the mid-1990s, HFMD infections caused by human enterovirus 71 (EV71) have resulted in significant morbidity and mortality, particularly in the Asia-Pacific region (Solomon, T et al., (2010) Lancet Infect Dis 10(11):778-90; and McMinn, PC (2002) FEMS Microbiol Rev 26: 91-107). China, Viet Nam, and Singapore reported increased activity in January-May 2012 compared to the same period in 2011. Hand, Foot, and Mouth Disease outbreaks disrupt education and economic activities due to school and childcare center closures in efforts to control disease transmission.
Human enterovirus A belongs to the Picornaviridae family of non-enveloped, positive-sense RNA viruses, which also includes polioviruses and rhinoviruses. Members of the HEV-A group which cause HFMD include Enterovirus 71(EV71) and Coxsackieviruses, including serotypes A1, A4, A6, A10, and A16 (Pallansch and Roos, (2007) Knipe D M, Howley P M, Griffin D E, editors. Fields Virology. Philadelphia, Pa. Lippincott Williams & Wilkins. pp. 839-894; and Kobayashi M et al., Jpn J Infect Dis 2013; 66:260-1). HFMD outbreaks due to EV71 infection have the greatest propensity to cause severe neurological disease. Experimental infection of cynomologus macaques showed that strains isolated across several decades were all neurotropic, as well as showing a broader tissue tropism than polioviruses (Nagata, N et al., (2002) J Med Virol 67: 207-216).
EV71 has four capsid proteins (VP1-VP4) and seven nonstructural proteins. In addition to protecting the viral RNA, the capsid proteins recognize receptors on the surface of host cells and contribute to the antigenic profile of the virus (Pallansch and Roos, (2007) Knipe D M, Howley P M, Griffin D E, editors. Fields Virology. Philadelphia, Pa. Lippincott Williams & Wilkins. pp. 839-894). Known human cell surface receptors for EV71 are the scavenger receptor B2 (SCARB2), and the P-selectin glycoprotein ligand 1 (PSGL-1) (Yamayoshi, S et al., (2009) Nat Med 15:798-801; and Nishimura, Y et al., (2009) Nat Med 15: 794-797).
Although the classical method of typing enteroviruses by serum neutralization defines EV71 as a single serotype [12], current molecular typing methods indicate that several genogroups have been circulating in the Asia-Pacific region at least since the 1990s (Lee, M S et al., (2012) PLoS Negl Trop Dis 6: e1737). EV71 isolates were previously classified into genogroups A, B, and C and sub-genogroups based on VP1 nucleotide sequences alone (Brown, B A et al., (1999) J Virol 73: 9969-9975); nucleotide sequence identity of the VP1 gene is >92% within genogroups, whereas nucleotide sequence identity between the genogroups is 78-83% (Solomon, T et al., (2010) Lancet Infect Dis 10(11):778-90). However, whole-genome sequencing resulted in the reclassification of subgenogroup B5 under B4 and addition of genogroup D; the authors suggested that the 3D polymerase sequence together with VP1 better represented whole genomes (Chan, Y F et al., (2009) Infect Genet Evol 10(3):404-12). Recombination between genogroups and with other Human enterovirus A serotypes also occurs (Yoke-Fun and AbuBakar (2006) BMC Microbiol 6: 74).
At present no specific antiviral therapy or vaccine against EV71 is available. Intravenous immunoglobulin has been used in severe HFMD cases, with some therapeutic benefit suggested by the outcomes but as yet unproven by clinical trials (Ooi, M H et al., (2009) BMC Infect Dis 9: 3; and Wang, S M et al., (1999) Clin Infect Dis 29: 184-190). Preventive and control measures during EV71 outbreaks are limited to surveillance, closure of educational and childcare facilities, and isolation of patients.